The rapid increase of knowledge in recent years about the molecular and cellular bases of immune regulation, particularly at the level of T cell responses, provides a new arsenal of immunotherapeutic approaches including the development of tumor vaccines. Certain monoclonal antibodies were shown to have immunomodulatory activity including the ability to bind determinants on the surface of T cells and to induce proliferation, activation, maturation or differentiation of these cells.
BAT (also referred to as mBAT-1 or BAT-1) is a murine monoclonal antibody generated against a membrane preparation of a Burkitt lymphoma cell line (Daudi) that was shown to exhibit antitumor and immunostimulatory effects towards various types of tumors (Hardy et al., 2001, Int. J. Oncol. 19:897). This monoclonal antibody was initially disclosed in U.S. Pat. No. 5,897,862 to Hardy et al. BAT-1 is secreted by the hybridoma cell line having CNCM Accession No. 1-1397.
The polynucleotide and amino-acid sequences of murine BAT are disclosed in WO 00/58363, to Hardy et al., and U.S. Patent Publication No. 2003/0026800. A number of humanized monoclonal antibodies based on murine BAT are disclosed in U.S. Patent Application Publication No. 2008/0025980. According to the disclosure, the humanized monoclonal BAT antibody appears to induce a greater antitumor effect than those induced by the parent murine BAT antibody. Among various model systems tested, the BAT antitumor activity was studied in SCID (severe combined immunodeficiency disease) mice, beige mice that are deficient in NK cells and nude mice that are deficient in T cells (Hardy, B., 1997, Proc. Natl. Acad. Sci. USA 94:5756). All mice were injected intravenously with murine B16 melanoma that subsequently develops tumors in the lungs. BAT exerted an antitumor effect only in SCID mice that were engrafted with either murine or human lymphocytes. In the athymic nude mice and the beige mice BAT exerted an antitumor activity, though this activity was less effective as compared to the antitumor activity of BAT in the wild-type mice.
The immunomodulatory effect of murine BAT was studied also in vitro. Murine BAT activates CD4+ T cells and induces the secretion of IFN-γ from these cells (Hardy et al., 2000, Int. Immunol. 12:1623 and Quaglino E. et al., 2005, Vaccine 9:23(25):3280-7, respectively). In addition, it was found that BAT triggers the proliferation of T cells and increases their cytolytic activity (Hardy, B. et al., 1997, Hum. Antibodies, 8:95).
Berger et al. (2008) discloses administration of the humanized monoclonal antibody CT-011, which is based on mBAT-1, to patients with advanced hematologic malignancies, and associated pharmacokinetics (Berger et al. Clin. Cancer Res. 2008; 14 (10) May 15, 2008).
It should be borne in mind that BAT antibodies are not expected to target the tumor cells themselves but rather the immune-functioning cells of the subject or patient, in order to modulate the immune response in a beneficial way.
One of the most widely used therapeutic treatments of cancer is chemotherapy. Chemotherapy drugs are divided into several groups based on their effect on specific chemical substances within cancer cells, the cellular activities or processes the drug interferes with, or the specific phases of the cell cycle the drug affects. Chemotherapy groups include: alkylating agents, nitrosoureas, antimetabolites, anthracyclines, topoisomerase I and II inhibitors, mitotic inhibitors and steroid inhibitors.
A chemotherapeutic drug may be provided as a sole therapy but is often used in combination with one or more other active agents. In some instances, specific combinations have been adapted to provide significantly better clinical results. For example, the antimetabolite fluorouracil (5FU) and the alkylating agent oxaliplatin, are used together in a combination regimen for the treatment of colorectal cancer. The combination therapy of fluorouracil, leucovorin (folinic acid) and oxaliplatin, also indicated for colorectal cancer, has been abbreviated as FOLFOX. The combination therapy of cyclophosphamide, doxorubicin, vincristine and predinisone (abbreviated as CHOP) is used for the treatment of non-Hodgkin lymphoma, and the combination of CHOP and the chimeric monolclonal antibody rituximab (abbreviated as R-CHOP) is used for the treatment of diffuse large B cell lymphoma and other aggressive B-cell non-Hodgkin lymphomas.
A combination therapy of uracil, 5FU or uracil mustard with radiation and with a monoclonal antibody, which specifically binds to an extracellular domain of a VEGF receptor, is disclosed in U.S. Pat. No. 6,811,779. This combined therapy is directed to inhibit angiogenesis. U.S. Pat. No. 6,217,866 discloses a method for inhibiting the growth of human tumor cells that express human EGF receptors comprising administering an effective amount of an anti-neoplastic agent and an effective amount of a monoclonal antibody to a human cancer patient having said tumor cells; (i) wherein said antibody binds to the extra-cellular domain of the human EGF receptor of said tumor cell; (ii) wherein the antibody is not conjugated to the anti-neoplastic agent; and (iii) wherein the antibody inhibits the binding of EGF to the EGF receptor.
Nowhere in the background art is it taught or suggested that use of a humanized mBAT-1 monoclonal antibody in combination with chemotherapy will be advantageous. In fact, since BAT and antibodies based thereon are known to have immunomostimulatory properties, it is highly surprising and unexpected that such antibodies in combination with cytotoxic or other chemotherapeutic drugs that act by killing proliferating cell populations can be used to achieve greater clinical efficacy than each type of agent on its own.